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To the Editor:

Treatment with selective serotonin reuptake inhibitors (SSRIs) during pregnancy requires additional data from well-designed studies. In the article, “Maternal use of selective serotonin reuptake inhibitors and risk of congenital malformations” by Wogelius et al,1 several positive methodologic choices deserve comment. These include the comprehensiveness of the linked prescription data and the Danish Medical Birth and hospital discharge registries, control for specific medications associated with congenital malformations, similar distribution of congenital malformation in this study with published data,2 and the large population-based sample.

However, several aspects of the methodology diminish the validity of the authors’ conclusion that SSRI exposure is associated with congenital malformations, much less causally related as claimed by their statement: the “observed association … was stronger [among patients with SSRI exposure during the second or third month after conception compared with exposure within the first trimester or 30 days before], which is consistent with a causal effect.” Because medication compliance and prescription length were not addressed, measurement of exposure was inexact—especially since SSRI treatment preconception and during the first month of gestation may affect the embryonic cell lines involved in organogenesis. Lacking an assessment of maternal depression severity biases their analyses since depression can directly impact fetal outcomes,3 and severity of depression may have even greater impact than drug exposure. Other researchers have studied similar relationships while more adequately controlling for important non-SSRI-related maternal factors.4,5 Controlled factors in these other studies included maternal demographics, prepregnancy body mass index or pregnancy weight gain, gravidity, medical histories, socioeconomic status, physiological and psychiatric comorbidities, smoking, alcohol, other substance use, concurrent medication and vitamin use. While Wogelius and colleagues consider some factors, other covariates of depression are excluded, which necessitates a more cautious interpretation of their results. Of note, the authors found that the rate of smoking was nearly twice as high among the SSRI group as compared with the non-SSRI group.6 Comorbid alcohol use, although directly associated with depression7 and congenital malformations in offspring,8 is not assessed. Additionally, the overlapping epochs used to define “early pregnancy” complicate the definition of exposure since the group with second or third month SSRI use appears to be a subgroup of patients using SSRI from preconception through the first trimester.

SSRI use during pregnancy remains a controversial public health issue. Publications on this topic must be subjected to careful scrutiny. Despite its strengths, the methodologic shortcomings of the Wogelius et al paper do not move the existing scientific literature forward.

Monique B. Kelly

Katherine L. Wisner

Marie D. Cornelius

Department of Psychiatry School of Medicine University of Pittsburgh Pittsburgh, PA kellymb2@upmc.edu